Troponyl-oxamic acid derivatives

ABSTRACT

Tropone derivatives characterized by having a derivative of oxamic acid at positions 2 and/or 5 are disclosed. In addition, the tropone nucleus can be optionally further substituted. The foregoing compounds are useful for preventing or treating allergic conditions in a mammal. Methods for the preparation and use of said compounds are disclosed.

BACKGROUND OF THE INVENTION

a. Field of the Invention

This invention relates to novel tropone derivatives, to processes fortheir preparation, to methods for using said derivatives, and totherapeutically acceptable salts and compositions of said derivatives.

More specifically, the present invention relates to noveltroponyl-oxamic acid derivatives possessing valuable pharmacologicproperties. For example, these derivatives are useful for preventing ortreating allergic conditions in a mammal at dosages which do not elicitundesirable side effects. The combination of these pharmacologicproperties render the troponyl-oxamic acid derivatives of the inventiontherapeutically useful.

B. Description of the Prior Art

A rather large number of reports dealing with tropone derivatives areavailable. The prior art relating to tropone derivatives is summarizedin various reviews; for example, see the review by F. Pietra in Chem.Rev., 73, 293 (1973). Another report describes a class of alkyl estersof 5-aminotropolones which exhibit anti-neoplastic activity, see L. D.Donaruma, Canadian Patent No. 787,451, issued June 11, 1968.

The tropone derivatives of the present invention are distinguished fromthe prior art compounds by the nature of the substituents on the troponenucleus and by their pharmacologic properties. More specifically, thenovel tropone derivatives of this invention are distinguished from theprior art compounds by having the tropone nucleus substituted with oneor two oxamic acid derivatives.

SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula I ##STR1## inwhich R¹ and R⁴ are the same or different selected from the groupconsisting of hydrogen, halo, trifluoromethyl, lower alkoxy, loweralkyl, phenyl, hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio, NR⁷ R⁸wherein R⁷ and R⁸ each is hydrogen or lower alkyl, or R⁷ is lower alkyland R⁸ is p-toluenesulfonyl, and a radical of formula NR⁹ COCOOR¹⁰wherein R⁹ and R¹⁰ each is hydrogen or lower alkyl; and R², R³, R⁵ andR⁶ are the same or different selected from the group consisting ofhydrogen, halo, trifluoromethyl, lower alkoxy, lower alkyl, phenyl,hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio, and NR⁷ R⁸ wherein R⁷and R⁸ each is hydrogen or lower alkyl; or R⁷ is lower alkyl and R⁸ isp-toluenesulfonyl; with the proviso that at least one of R¹ and R⁴ mustbe a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ and R¹⁰ are as definedherein.

A preferred group of compounds of formula I are those in which at leastthree or R¹, R², R³, R⁴, R⁵ and R⁶ are hydrogen.

Another preferred group of compounds of this invention is represented byformula I in which

a. R¹ is a radical of formula NR⁹ COCOOR¹⁰ in which R⁹ and R¹⁰ are thesame or different and are hydrogen or lower alkyl, and R², R³, R⁴, R⁵and R⁶ are the same or different selected from the group consisting ofhydrogen, lowr alkoxy and hydroxy; or

b. R⁴ is a radical of formula NR⁹ COCOOR¹⁰ in which R⁹ and R¹⁰ each ishydrogen or lower alkyl and R¹, R², R³, R⁵ and R⁶ are the same ordifferent selected from the group consisting of hydrogen, lower alkoxyand hydroxy; or

c. R¹ and R⁴ are a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ and R¹⁰each is hydrogen or lower alkyl, and R², R³, R⁵ and R⁶ are the same ordifferent selected from the group consisting of hydrogen, lower alkoxyand hydroxy.

Still another preferred group of compounds of this invention arerepresented by formula I in which

a. R¹ is a radical of formula NR⁹ COCOOR¹⁰ in which R⁹ and R¹⁰ each ishydrogen or lower alkyl, and R², R³, R⁴, R⁵ and R⁶ are the same ordifferent selected from the group consisting of hydrogen, lower alkoxyand hydroxy , with the proviso that at least three of R², R³, R⁴, R⁵ andR⁶ are hydrogen; or

b. R⁴ is a radical of formula NR⁹ COCOOR¹⁰ in which R⁹ and R¹⁰ each ishydrogen or lower alkyl, and R¹, R², R³, R⁵ and R⁶ are the same ordifferent selected from the group consisting of hydrogen, lower alkoxyand hydroxy, with the proviso that at least three of R¹, R², R³, R⁵ andR⁶ are hydrogen; or

c. R¹ and R⁴ are a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ and R¹⁰each is hydrogen or lower alkyl; and R², R³, R⁵ and R⁶ are the same ordifferent selected from the group consisting of hydrogen, lower alkoxyand hydroxy, with the proviso that at least two of R², R³, R⁵ and R⁶ arehydrogen.

The therapeutically acceptable salts of the compounds of formula I arealso included within the scope of this invention.

The compounds of this invention of formula I are prepared by a processcomprising: condensing a compound of formula II ##STR2## in which R¹¹and R¹⁴ are the same or different selected from the group consisting ofhydrogen, halo, trifluoromethyl, lower alkoxy, lower alkyl, phenyl,hydroxy phenoxy, mercapto, (2-carboxyphenyl)thio, NR⁷ R⁸ wherein R⁷ islower alkyl and R⁸ is hydrogen, lower alkyl or p-toluenesulfonyl, andNHR⁹ wherein R⁹ is hydrogen or lower alkyl; and R¹², R¹³, R¹⁵ and R¹⁶are the same or different selected from the group consisting ofhydrogen, halo, trifluoromethyl, lower alkoxy, lower alkyl, phenyl,hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio, and NR⁷ R⁸ wherein R⁷is lower alkyl and R⁸ is hydrogen, lower alkyl or p-toluenesulfonyl;with the priviso that at least one of R¹¹ and R¹⁴ must be NHR⁹, with acompound of formula III

    halogen--COCOOR.sup.10                                     (III)

in which R¹⁰ is lower alkyl and the halogen is bromine, chlorine oriodine in the presence of a proton acceptor to obtain the correspondingcompound of formula I in which R¹ and R⁴ are the same or differentselected from the group consisting of hydrogen, halo, trifluoromethyl,lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy, mercapto,(2-carboxyphenyl)thio and NR⁷ R⁸ wherein R⁷ is lower alkyl and R⁸ ishydrogen, lower alkyl or p-toluenesulfonyl, and a radical of formula NR⁹COCOOR¹⁰ wherein R⁹ is as defined herein and R¹⁰ is lower alkyl; and R²,R³, R⁵ and R⁶ are the same or different selected from the groupconsisting of hydrogen, halo, trifluoromethyl, lower alkoxy, loweralkyl, phenyl, hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio and NR⁷R⁸ wherein R⁷ is lower alkyl and R⁸ is hydrogen, lower alkyl orp-toluenesulfonyl; and, if desired and required, followed bytransformation of the compound of formula I, prepared as describedabove, to other compounds of formula I by methods described herein.

Another aspect of this invention involves a pharmaceutical compositioncomprising a compound of formula I or a therapeutically acceptableaddition salt thereof, and a pharmaceutically acceptable carriertherefor.

Still another aspect of this invention involves a method for preventingor treating allergic conditions in a mammal which comprisesadministering to said mammal an effective allergy alleviating amount ofa compound of formula I or a therapeutically acceptable addition saltthereof.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight andbranched chain alkyl radicals containing from one to six carbon atomsand includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl and the like.

The term "lower alkoxy" as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to six carbon atomsand includes methoxy, ethoxy, isopropoxy, butoxy, hexanoxy and the like.

The terms "halogen" and "halo" as used herein contemplate halogens andinclude fluorine, chlorine, bromine and iodine, unless stated otherwise.

The term "lower alkanol" as used herein contemplates both straight andbranched chain alkanols containing from one to six carbon atoms andincludes methanol, ethanol, isopropanol, butanol, hexanol and the like.

The acidic compounds of formula I in which R¹ and/or R⁴ is a radical offormula NR⁹ COCOOR¹⁰ wherein R¹⁰ is hydrogen form salts with suitabletherapeutically acceptable inorganic and organic bases. These derivedsalts possess the same activity as the parent acid and are includedwithin the scope of this invention. The acid is transformed in excellentyield into the corresponding therapeutically acceptable salt byneutralization of said acid with the appropriate inorganic or organicbase. The salts are administered in the same manner as the parent acidcompounds. Suitable inorganic bases to form these salts include, forexample, the hydroxides, carbonates, bicarbonates or alkoxides of thealkali metals or alkaline earth metals, for example, sodium, potassium,magnesium, calcium and the like. Suitable organic bases include thefollowing amines; lower mono-, di- and trialkylamines , the alkylradicals of which contain up to three carbon atoms, such as methylamine,dimethylamine, trimethylamine, ethylamine, di- and triethylamine,methylethylamine, and the like; mono-, di and trialkanolamines, thealkanol radicals of which contain up to three carbon atoms, for example,mono-, di- and triethanolamine; alkylene-diamines which contain up tosix carbon atoms, such as hexamethylenediamine; cyclic saturated orunsaturated bases containing up to six carbon atoms, such aspyrrolidine, piperidine, morpholine, piperazine and their N-alkyl andN-hydroxyalkyl derivatives, such as N-methyl-morpholine andN-(2-hydroxyethyl)piperidine, as well as pyridine. Furthermore, theremay be mentioned the corresponding quaternary salts, such as thetetraalkyl (for example tetramethyl), alkyl-alkanol (for examplemethyltrimethanol and trimethyl-monoethanol) and cyclic ammonium salts,for example the N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)morpholinium, N,N-dimethylmorpholinium,N-methyl-N-(2-hydroxyethyl)morpholinium, N,N-dimethylpiperidinium salts,which are characterized by having good water-solubility. In principle,however, there can be used all the ammonium salts which arephysiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the acid for formula I in watercontaining at least one equivalent amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. Advantageously,the reaction is performed in a water-miscible, inert organic solvent,for example, methanol, ethanol, dioxane, and the like in the presence ofwater. For example, such use of sodium hydroxide, sodium carbonate orsodium bicarbonate gives a solution of the sodium salt. Evaporation ofthe solution or addition of a water-miscible solvent of a more moderatepolarity, for example, a lower alkanol, for instance, butanol, or alower alkanone, for instance, ethyl methyl ketone, gives the solidinorganic salt if that form is desired.

To produce an amine salt, the acid of formula I is dissolved in asuitable solvent of either moderate or lower polarity, for example,ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthen added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of lower polarity, for example, benzene or petroleum ether, orby evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use substantiallyequivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid of formula I with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

The basic compounds of formula I in which R¹, R², R³, R⁴, R⁵ and/or R⁶is NR⁷ R⁸ wherein R⁷ and R⁸ are as defined herein form addition saltswith suitable inorganic and organic acids. These salts possess the sameactivities as the parent base compound when administered to a mammal andmay be utilized in the same manner. Suitable acids to form these saltsinclude, for example the common mineral acids, hydrophalic, sulfuric orphosphoric, as well as the organic acids, formic, acetic, maleic, malic,citric, or tartaric acid, or acids which are sparingly soluble in bodyfluids and which impart slow-release properties to their respectivesalts such as pamoic or tannic acid or carboxymethyl cellulose. Theaddition salts thus obtained are the functional equivalent of the parentbase compound in respect to their therapeutic use. Hence, these additionsalts are included within the scope of this invention and are limitedonly by the requirement that the acids employed in forming the salts betherapeutically acceptable.

Also included within the scope of this invention are the isomers of thecompounds of formula I resulting from the asymmetric centers containedtherein.

Also included within the scope of this invention are the tautomericforms of the compounds of formula I in which R¹, R², R³, R⁴, R⁵ and/orR⁶ is hydroxy resulting from the keto-enol equilibrium containedtherein.

Anti-allergic Activity

The compounds of this invention of formula I or therapeuticallyacceptable salts thereof are useful in the prevention or treatment ofallergic reactions in a mammal upon oral or parenteral administration.

More specifically, the compounds of this invention are useful for theprophylactic treatment as well as for the management of anaphylacticreactions and atopic allergic manifestations, for example, bronchialasthma, hay fever, allergic rhinitis, allergic conjunctivitis, foodallergies, urticaria and the like, in a sensitized mammal.

More specifically exemplified, the compounds of this invention areeffective anti-allergic agents when tested using the passive cutaneousanaphylaxis (PCA) method, described by I. Mota, Immunology, 7,681(1964). The anti-allergic activity of a given compound is measured inrats by its ability to inhibit the increase in vascular permeability atthe site of injection of rat immunoglobulin E (IgE) followed by i.v.administration of the specific antigen. Evans blue is injected i.v. atthe same time as the specific antigen, and the size of the wheal or ofthe area infiltrated with Evans blue is measured and compared with thatof untreated controls. An effective anti-allergic agent will prevent orinhibit the release of inflammatory mediators (mainly serotonin andhistamine from the mast cells) which causes an increase in vascularpermeability and thus an infiltration of Evans blue surrounding the siteof injection of IgE. The anti-allergic activity of the compounds offormula I is demonstrated by the reduction of the wheal size ofsensitized skin tissue compared to that of control animals. A comparisonof the anti-allergic activity of the compounds of this invention withthe anti-allergic activity of a standard compound, such as disodiumcromoglycate, indicates that the compounds of this invention function inthe same manner as disodium cromoglycate by blocking the release ofmediators from the mast cells responsible for the allergic reaction.

When the compounds of formula I of this invention are used forsuppressing allergic manifestations of anaphylactic reactions and atopichypersensitivity in a mammal, they are used alone or in combination withpharmacologically acceptable carriers, the proportion of which isdetermined by the solubility and the chemical nature of the compound,chosen route of administration and standard biological practice. Forexample, they are administered parenterally by injection; orally; by thenasal route, for instance, as drops or aerosol; or by inhalation from anaerosol.

In addition, the compounds of this invention can be administered inconjunction with common anti-allergics, for example, known compoundseffecting anti-histaminic, analgesic, central nervous system depressant,anti-hypertensive, immunosupressive, anti-bradykinin, anti-serotonin orendocrinological responses.

Therapeutic compositions containing the compounds of this invention areeffective anti-allergic agents for preventing or relieving anaphylacticallergic manifestations at dosages of 0.1 mg to 100 mg/kg body weightwhen administered parenterally to a mammal. For administration to amammal by parenteral injection, it is preferred to use the compounds offormula I in solution in a sterile aqueous vehicle which may alsocontain other solutes such as buffers or preservatives, as well assufficient quantities of pharmaceutically acceptable salts or of glucoseto make the solution isotonic.

A number of the compounds of this invention of formula I are useful inthe management of allergic reactions when administered orally at dosagesof 0.5 mg to 500 mg/kg body weight to a sensitized mammal. For example,the representative compounds of formula I,

[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester(see Example 1),

[N-(2-oxo-3,5,7-cycloheptatrien-1-yl)-N-methylamino]oxo-acetic acidethyl ester (see Example 1),

2,2'-[(2-oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-aceticacid] diethyl ester (see Example 6),

[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid pentyl ester(see Example 31) and

[(5-methoxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid1-methylethyl ester (see Example 31),

are effective anti-allergic agents when administered orally at dosagesof 1.0 mg to 100 mg/kg body weight.

When the compounds of this invention are employed as anti-allergicagents in mammals, e.g. rats, orally effective, anti-allergic amounts ofthe compounds are administered to the mammal, either alone or combinedwith pharmaceutically acceptable excipients in a dosage form, i.e.capsule or tablet, or the compounds are administered orally in the formof solutions or suspensions.

The tablet compositions contain the active ingredient in admixture withnon-toxic pharmaceutical excipients known to be suitable in themanufacture of tablets. Suitable pharmaceutical excipients are, forexample, starch, milk sugar, certain types of clay and so forth. Thetablets may be uncoated or they may be coated by known techniques so asto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period.

The aqueous suspensions of the invention contain the active ingredientin admixture with one or more non-toxic pharmaceutical excipients knownto be suitable in the manufacture of aqueous suspensions. Suitableexcipients are, for example, methylcellulose, sodium alginate, gumacacia, lecithin and so forth. The aqueous suspensions may also containone or more preservatives, one of more coloring agents, one or moreflavoring agents and one or more sweetening agents.

Non-aqueous suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example, arachis oil, olive oil,sesame oil, or coconut oil, or in a mineral oil, for example liquidparaffin, and the suspension may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. These compositions may alsocontain a sweetening agent, a flavoring agent and an anti-oxidant.

The compounds of formula I can also be administered as nasal powders orinsufflations. For such purpose the compounds are administered in finelydivided solid form together with a pharmaceutically acceptable solidcarrier, for example, a finely divided polyethylene glycol ("Carbowax1540") or finely divided lactose. Such compositions may also containother excipients in finely divided solid form, for instance,preservatives, buffers, or surface active agents.

When administering the compounds of this invention by inhalation from anaerosol, the compound of formula I is dissolved in water or ethanol andmixed with a volatile propellant, for example, dichlorotetrafluoroethaneand dichlorodifluoromethane, and placed in a pressurized containerhaving a metering valve to release a predetermined amount of material.

The dosage of the compounds of this invention will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstance is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects, and preferably at alevel that is in a range of from about 0.1 mg to about 500 mg perkilogram body weight, although as aforementioned variations will occur.However, a dosage level that is in the range of from about 0.5 mg toabout 200 mg per kilogram body weight is most desirably employed inorder to achieve effective results.

Processes

Useful and practical starting materials for the preparation of thecompounds of this invention of formula I are the tropone derivatives offormula II ##STR3## in which R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are asdefined in the first instance.

The tropone derivatives of formula II suitable as starting materials aredescribed in a number of reports; for example, see the recent review ontropone derivatives, their preparation and their interconversions by F.Pietra, supra. Thus, the tropone derivatives suitable as startingmaterials are either known or they can be prepared by conventionalmeans.

The compounds of this invention of formula I are prepared by condensingthe compound of formula II in which R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ areas defined in the first instance with one to ten molar equivalents,preferably one to three molar equivalents, of a compound of formula III.

    halogen--COCOOR.sup.10                                     (III)

in which R¹⁰ is lower alkyl and the halogen is bromine, chlorine oriodine in the presence of a proton acceptor to obtain the correspondingcompound of formula I in which R¹ and R⁴ are the same or differentselected from the group consisting of hydrogen, halo, trifluoromethyl,lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy, mercapto,(2-carboxyphenyl)thio and NR⁷ R⁸ wherein R⁷ is lower alkyl and R⁸ ishydrogen, lower alkyl or p-toluenesulfonyl, and a radical of formula NR⁹COCOOR¹⁰ wherein R⁹ is as defined herein and R¹⁰ is lower alkyl; and R²,R³, R⁵ and R⁶ are the same or different selected from the groupconsisting of hydrogen, halo, trifluoromethyl, lower alkoxy, loweralkyl, phenyl, hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio and NR⁷R⁸ wherein R⁷ is lower alkyl and R⁸ is hydrogen, lower alkyl orp-toluenesulfonyl.

In practicing the above condensation it is preferable to use an inertsolvent as a reaction medium. Suitable solvents include benzene,toluene, chloroform, methylene chloride, lower alkyl ketones (i.e.2-propanone, 2-butanone and 3-pentanone) and the like. However, if thereactants are mutually soluble, the solvent can be omitted withoutdeleterious effects.

Suitable proton acceptors include the organic bases, or amines forinstance, triethylamine, pyridine, N-ethylmorpholine,1,5-diazabicyclo[3.4.0]nonene-5 and the like, as well as the inorganicbases, preferably the alkali metal hydroxides, carbonates, hydrides,amides and alkoxides, for example, sodium ethoxide, sodium hydroxide,potassium hydroxide, potassium carbonate, sodium methoxide and the like.The preferred proton acceptors employed are the organic bases or amines.The amount of the organic bases can vary from one molar equivalent to alarge molar excess. When a large molar excess is used, the organic basecan also serve as the solvent for the condensation.

The duration and temperature of the condensation are not critical;however, the preferred time is from about ten minutes to about 2 daysand the temperature can range from about -10° C to 100° C or the boilingpoint of the reaction mixture, preferably from about 20° C to theboiling point of the reaction mixture. The compounds of formula I areseparated from the reaction mixture by conventional means, for example,evaporation, filtration, extraction, chromatography and/orcrystallization.

The compounds of formula I obtained from the above describedcondensation can be further reacted to obtain other compounds of formulaI by methods described hereinafter.

For instance the compound of formula I in which at least one of R¹, R²,R³, R⁴, R⁵ and R⁶ is lower alkoxy or halo can be reacted with a molarexcess of ammonia or an amine of formula HNR⁷ R⁸ in which R⁷ and R⁸ areas defined herein to obtain the corresponding compound of formula I inwhich at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is NR⁷ R⁸ in which R⁷and R⁸ are as defined herein. The reaction is conducted either using theamine of formula HNR⁷ R⁸ as solvent or a suitable solvent can beselected from water and a lower alkanol (i.e. methanol, ethanol and thelike). Suitable conditions for the reaction are a temperature of fromabout -50° C to about 100° C, preferably 0° to 100° C, for about tenminutes to 12 hours. If the temperature necessary for reaction is abovethe boiling point of the reaction mixture, the reaction can be conductedat the desired temperature in a pressure vessel without deleteriouseffects.

The compound of formula I, prepared as above, in which at least one ofR¹ and R⁴ is a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ is as definedherein and R¹⁰ is lower alkyl can be hydrolyzed to obtain thecorresponding acidic compound of formula I in which the corresponding R¹and R⁴ is a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ is as definedherein and R¹⁰ is hydrogen. The preferred method of hydrolysis comprisesthe use of 0.1 to 2.0 molar equivalents, preferably 0.5 to 1.0 molarequivalents, of a mild alkali, for example a suitable mild alkaliselected from the bicarbonates and acetates of sodium or potassium, inan inert solvent, for instance, water, a lower alkanol (i.e. methanol orethanol) or mixtures thereof, at a temperature of about 20° to 120° Cfor about 1 to 10 hours. Acidification of the reaction mixture with adilute mineral acid, such as hydrochloric acid, sulfuric acid,phosphoric acid and the like, gives the corresponding acidic compound offormula I.

In addition, a number of the compounds of formula I are readilyconverted to other compounds of formula I. In some cases it isconvenient and preferable to prepare a specific compound of formula I bythe transformation of another compound of formula I. Examples of suchinterconversions of the compound of formula I are described hereinafter.

For example, the acidic compound of formula I described above (i.e. R¹and/or R⁴ is a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ is as definedherein and R¹⁰ is hydrogen) is readily esterified to obtain thecorresponding ester of formula I (i.e. R¹ and/or R⁴ is a radical offormula NR⁹ COCOOR¹⁰ wherein R⁹ is as defined herein and R¹⁰ is loweralkyl). Suitable esterification conditions include a variety of methods;for example, ester exchange, treatment with diazomethane, or conversionof the acid to the corresponding activated carbonyl (i.e., acid halide,anhydride, succinimio, imidazolide and the like), followed by treatmentof the latter with an appropriate lower alkanol, see also L. F. Fieserand M. Fieser, "Advanced Organic Chemistry," Reinhold PublishingCorporation, New York 1961, pp. 370-381.

A preferred and convenient method of esterification comprises dissolvingthe acidic compound of formula I in an inert solvent, preferablydimethylsulfoxide, in the presence of one to ten molar equivalents of amild base, for example, sodium or potassium carbonate. One to threemolar equivalents of a lower alkyl bromide or chloride is added and thesolution is maintained at a temperature of about 20° to 100° C,preferably at about 40° to 80° C, for about 30 minutes to 5 hours.

The compound of formula I in which at least one of R¹, R², R³, R⁴, R⁵and R⁶ is hydroxy can be alkylated to obtain the corresponding compoundof formula I in which the corresponding R¹, R², R³, R⁴, R⁵ and R⁶ isalkoxy. The alkylation is conveniently carried out by reacting saidhydroxy compound with one to five molar equivalents of a di(lower)alkylsulfate in the presence of one to five molar equivalents of a mildalkali, for instance sodium or potassium carbonate in an inert solvent,for example, a lower alkyl ketone, preferably 2-butanone, 2-propanoneand the like. The alkylation is conducted at a temperature from about30° C to the boiling point of the reaction mixture for about 30 minutesto ten hours.

A useful alternative method of esterification or alkylation comprisesreacting the acidic or hydroxy compound of formula I with an excess of adiazoalkane, for instance diazomethane, diazoethane and the like, in aninert solvent, e.g. diethyl ether or methanol.

The compound of formula I in which at least one of R¹, R², R³, R⁴, R⁵and R⁶ is lower alkoxy, chlorine, bromine or iodine can be reacted withsodium sulfhydrate in an inert solvent, preferably a lower alkanol (i.e.methanol, ethanol and the like) to obtain the corresponding compound offormula I in which the corresponding R¹, R², R³, R⁴, R⁵ and R⁶ ismercapto. This reaction is preferably carried out at a temperature offrom about -70° C to about 30° C for about 1 to 10 hours.

The following examples illustrate further this invention.

EXAMPLE I [(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid EthylEster; I (R¹ = NH-CO-COOC₂ H₅ and R², R³, R⁴, R⁵ and R⁶ = H)

A solution of ethyl oxalyl chloride (0.30 g) in pyridine (15 ml) isadded to a solution of 2-amino-2,4,6-cycloheptatrien-1-one [0.242 g,described by T. Nozoe et al., Proc. Japan Acad. 27, 556-560 (1951), CA46, 7559 g] in pyridine (0.5 ml). The mixture is heated until a solutionforms and the solution is stirred at room temperature for 45 minutes.Water is added and collection of the precipitate gives the titlecompound, mp 114° C.

In the same manner but replacing 2-amino-2,4,6-cycloheptatrien-1-onewith an equivalent amount of 2-methylamino-2,4,6-cycloheptatrien-1-one[described by N. Soma et al., Chem. Pharm. Bull., 13, 457-64 (1965)],[N-(2-oxo-3,5,7-cycloheptatrien-1-yl)-N-methylamino]oxo-acetic acidethyl ester, mp 70°-71° C, is obtained.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

EXAMPLE 2 [(3-Bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-aceticAcid Ethyl Ester; I (R¹ = NH-CO-COOC₂ H₅ ; R², R³, R⁴ and R⁵ = H and R⁶= Br)

A solution of 7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one [1.0 g,described by T. Nozol et al., Proc. Japan Acad., 27, 556-60 (1951), (CA46, 7560c)] in methanol (30 ml) is cooled to -20° C and saturated withgaseous ammonia. The reaction mixture is heated in a pressure bottle at80° C for 4 hours and cooled to -70° C. The bottle is opened and thesolvent is removed under reduced pressure. The residue is boiled withethyl acetate and the ethyl acetate extract is evaporated to give2-amino-7-bromo-2,4,6-cycloheptatrien-1-one.

A solution of the latter compound (0.800 g) in pyridine (10 ml) iscooled to 0° C and ethyl oxalyl chloride (0.544 g) is added dropwise.The mixture is stirred at 0° C for 1 hour and at room temperature for 2hours. The solvent is removed under reduced pressure and the residue iscrystallized from methanol-acetone to give the title compound, mp161°-163° C.

In the same manner but replacing7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one with an equivalent amountof 5-chloro-2-methoxy-2,4,6-cycloheptatrien-1-one [described by T. Sato,Nippon Kagaku Zasski, 80, 1171-4 (1959), (CA 55, 4389c)],[(5-chloro-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, mp 178°-179° C, is obtained.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

EXAMPLE 3 [(3-Phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-aceticAcid Ethyl Ester; 1 (R¹ = NH-CO-COOC₂ H₅ ; R², R³, R⁴ and R⁵ = H and R⁶= OC₆ H₅)

a. A mixture of 2-hydroxy-3-phenoxy-2,4,6-cycloheptatrien-1-one [13.0 g,described by Y. Kitahara, Sci. Repts. Tohoku Univ. First Ser., 39,265-74 (1956), (CA 51, 12874f)], potassium carbonate (28.9 g),dimethylsulfate (26.5 g) and methyl ethyl ketone (680 ml) is heated atreflux for two hours. The hot mixture is filtered and the filtrate isevaporated under reduced pressure. The residue is subjected tochromatography on silica gel using ether. The appropriate fractions ofthe eluate are combined and evaporated to give2-methoxy-3-phenoxy-2,4,6-cycloheptatrien-1-one and2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one.

b. A solution of 2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one (2.0 g,described above) in methanol (30 ml) is cooled to -25° C and saturatedwith gaseous ammonia. The mixture is heated in a pressure bottle at 80°C for 4 hours and cooled to -70° C. The bottle is opened and the solventis removed under reduced pressure. The residue is crystallized fromethyl acetate to give 2-amino-7-phenoxy-2,4,6-cycloheptatrien-1-one.

In the same manner but replacing2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one with an equivalentamount of 2-methoxy-3-phenoxy-2,4,6-cycloheptatrien-1-one [describedabove in (a)], 2-amino-3-phenoxy-2,4,6-cycloheptatrien-1-one isobtained.

c. A solution of 2-amino-7-phenoxy-2,4.6-cycloheptatrien-1-one [1.38 g,described above in (b)] in pyridine (50 ml) is cooled to 0° C and ethyloxalyl chloride (0.980 g) is added dropwise. The mixture is stirred at0° C for 1 hour and at room temperature for 2 hours. Most of the solventis removed under reduced pressure and water (200 ml) is added. Theprecipitate is collected and crystallized from ethyl acetate to give thetitle compound, mp 145°-145.5° C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

In the same manner but replacing2-amino-7-phenoxy-2-amino-3-phenoxy-2,4,6-cycloheptatrine-1-one[described above in (b))], [(7-phenoxy-2-oxo-3,5,7-cycloheptatrien-1-oneyl)amino]oxo-acetic acid ethyl ester, mp 121°-122° C, is obtained.

EXAMPLE 4 8 (5-Hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-aceticAcid Ethyl Ester; I (R¹ = OH, R², R³, R⁵ and R⁶ = H and R⁴ =NH-CO-COOC₂H₅)

Ethyl oxalyl chloride (1.36 g ) is added dropwise to a solution at 0° Cof 5-amino-2-hydroxy-2,4,6-cycloheptatrien-1-one [0.680 g, described byT. Nozoe et al., Sci. Repts. Tohoku Univ. 1, 35, 274-82 (1952)] inpyridine (15 ml). After 30 min. the reaction mixture is allowed to reachroom temperature. The solvent is removed under reduced pressure and theresidue is dissolved in methylene chloride. The solution is washed withwater, dried, evaporated and the residue is crystallized from ethylacetate to give the title compound,mp 186°-187° C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of ethyl oxalyl bromide, the title compound isobtained.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount oxalyl chloride or propyl oxalyl bromide[(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl]amino]oxo-acetic acidmethyl ester and[(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidpropyl ester are obtained respectively.

EXAMPLE 5 [(3-Hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-aceticAcid Ethyl Ester; 1 (R¹ = NH-CO-COOC₂ H₅ ; R², R³, R⁴ and R⁵ = H and R⁶= OH

The hot solutions of 3-bromo-2-hydroxy-2,4,6-cycloheptatriene-1-one(30.0 g) in methanol (2000 ml) and cupric accetate (18.0 g) in methanol(2000 ml) are mixed and the precipitate is collected to give3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1 -one copper complex.

A mixture of the latter compound (11.65 g), potassiump-toluenesulfonamide (15.7 g) and pyridine (150 ml) is heated at refluxfor 16 hours. The pyridine is evaporated under reduced pressure andchloroform is added to the residue. The precipitate is collected andwashed with chloroform. The precipitate is suspended in chloroform and2N sulfuric acid (40 ml) followed by the addition of hydrogen sulfidegas until the copper complex is decomposed. The precipitate is removedby filtration and the organic phase of the filtrate is separated. Theorganic phase is dried over sodium sulfate and evaporated. The residueis mixed with methanol and the precipitate is collected to obtain2-hydroxy-3-[[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one,mp 177°-179° C.

A solution of the latter compound (5.0 g) in conc. sulfuric acid (25 ml)is stirred at room temperature for 16 hours. The solution is poured onice, neutralized with sodium carbonate and extracted with chloroform.The solvent is removed by evaporation to give a residue of3-amino-2-hydroxy-2,4,6-cycloheptatrien-1-one [the latter compound isdescribed in Sci. Repts. Tohoku Univ. First Ser., 39, 83-91 (1956)].

To a solution of the latter compound (1.19 g) and triethylamine (1.1 g)in methylene chloride (25 ml) at room temperature, ethyl oxalyl chloride(1.27 g) in methylene chloride (5 ml) is added dropwise. The mixture isstirred for four hours and washed with water. The organic phase is driedover sodium sulfate and evaporated. The residue crystallized from ethylacetate to give the title compound, mp 158°-159° C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

EXAMPLE 62,2'[(2-Oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-aceticacid] Diethyl Ester; I (R¹ and R⁴ = NH-CO-COOC₂ H₅ and R², R³, R⁵ and R⁶= H)

Conc. ammonium hydroxide solution (50 ml) is added dropwise to asuspension of 2-hydroxy-5-nitroso-2,4,6-cycloheptatrien-1-one [10 g,described by T. Nozoe et al., Sci. Repts. Tohoku Univ., 35, 274-82(1952), (CA 47 329la)] collected and washed with water then acetone togive 2-amino-5-nitroso-2,4,6-cycloheptatrien-1-one.

A mixture of the latter compound (5.0 g) and 5% palladium on charcoal(1.5 g) in ethanol (2000 ml) is stirred rapidly under an atmosphere ofhydrogen for 12 minutes (hydrogen absorbed is 1600 ml). The mixture isfiltered and the filtrate is evaporated to give2,5-diamino-2,4,6-cycloheptatrien-1-one.

The latter compound is dissolved in pyridine (150 ml), cooled to 0° Cand ethyl oxalyl chloride (9.55 g) is added dropwise. The reactionmixture is warmed to room temperature and stirred for two hours. Half ofthe pyridine is evaporated under reduced pressure and the residue isadded to water (400 ml). The precipitate is collected, crystallized fromethyl acetate and subjected to chromatography on silica gel using ethylacetate for elution. The eluates are evaporated and the residue iscrystallized from ethyl acetate to give the title compound, mp 217°-218°C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl choride, the methyl andpropyl esters of the title compound are obtained.

EXAMPLE 7 [(6-Methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-aceticAcid Ethyl Ester; I (R¹ = NH-CO-COOC₂ H₅ ; R², R⁴, R⁵ and R⁶ = H and R³= OCH₃)

a. A solution of 3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1-one [27.5 g,described by T. Toda et al., Nippon Hagaku Zasshi, 88, 1234-5 (1967),(CA 68 101342)] and sodium methoxide (prepared from 12.6 g of sodium inmethanol followed by evaporation of the methanol) in dimethyl sulfoxide(300 ml) is heated at 80° C for 1 hour. The solution is cooled poured onice, acidified with 2N sulfuric acid and extracted with ethyl acetate.The organic extract is washed with brine, dried over sodium sulfate andevaporated. The residue is crystallized from ethyl acetate-hexane togive 2-hydroxy-3-methoxy-2,4,6-cycloheptatrien-1-one. Evaporation of themother liquors gives 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one.

b. A mixture of 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one(described above, 13 g), potassium carbonate (23.6 g), dimethyl sulfate(21.6 g) and 2-butanone (130 ml) is heated at reflux for 3 hours. Themixture is filtered and the filtrate is evaporated. The residue issubjected to chromatography on silica gel using acetone-ethyl acetate(1:1) and evaporation of the eluates gives2,4-dimethoxy-2,4,6-cycloheptatrien-1-one and2,6-dimethoxy-2,4,6-cycloheptatrien-1-one.

In the same manner but replacing2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one with an equivalentamount of 2-hydroxy-3-methoxy-2, 4,6-cycloheptatrien-1-one [(describedabove in (a)], 2,3-dimethoxy-2,4,6-cycloheptatrine-1-one and2,7-dimethoxy-2,4,6-cycloheptatrine-1-one are obtained.

c. A solution of 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one [describedabove in (b),2.4 g] in methanol (70 ml) is cooled to -25° C andsaturated with ammonia gas. The solution is heated in a pressure bottleat 80° C for 4 hours and cooled to -70° C. The pressure bottle is openedand the solvent is evaporated to give2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one.

In the same manner but replacing2,4-dimethoxy-2,4,6-cycloheptatrien-1-one with an equivalent amount of2,6-dimethoxy-2,4,6-cycloheptatrien-1-one with an equivalent amount of2,6-dimethoxy-2,4,6cycloheptatrien-1-one or2,3-dimethoxy-2,4,6-cycloheptatrien-1one,2-amino-6-methoxy-2,4,6-cycloheptatrien-1-one and2-amino-3-methoxy-2,4,6-cycloheptatrien-1-one are obtained,respectively.

d. A solution of ethyl oxalyl chloride (2.16 g) in methylene chloride(25 ml) is added dropwise to a solution of2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one [described above in (c),2.9 g] and triethylamine (1.84 g) in methylene chloride (50 ml). Themixture was stirred at room temperature for 3 hours, washed with water,dried over sodium sulfate and evaporated. The residue is subjected tochromatography on silica gel using ethyl acetate-hexane (2:3). Theeluates are evaporated to give the title compound, mp 132°-134° C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

In the same manner but replacing2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one with an equivalent amountof 2-amino-6-methoxy-2,4,6-cycloheptatrien-1-one or2-amino-3-methoxy-2,4,6-cycloheptatrien-1-one,[(4-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, mp 157°-158° C, and[(7-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester are obtained, respectively.

In the same amount but replacing dimethyl sulfate with an equivalentamount of diethyl sulfate,[(6-ethoxy-2-oxo-3,5,7-cycloheptatrien-1yl)amino]oxo-acetic acid ethylester is obtained.

EXAMPLE 8[[7-Oxo-4-[(2-carboxyphenyl)thio]-1,3,5-cycloheptatrien-1-yl]amino]oxoaceticacid Ethyl Ester; I (R¹ = NH-CO-COOC₂ H₅ ; R², R³, R⁵ and R⁶ = H and R⁴= 2-carboxyphenylthio)

A solution of5-[(2-carboxyphenyl)thio]-2-methoxy-2,4,6-cycloheptatrien-1-one (1.0 g,prepared from 5-chloro-2-methoxy-2,4,6-cycloheptatrien-1-one and2-mercaptobenzoic acid) in methanol (30 ml) at -25° C is saturated withammonia gas. The solution is heated in a pressure bottle at 80° C for 8hours and cooled to -70° C. The bottle is opened and the solvent isevaporated to give2-amino-5-[(2-caboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one.

A solution of ethyl oxalyl chloride (1.0 g) in methylene chloride (10ml) is added dropwise to a suspension of2-amino-5-[(2-carboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one (1.0 g)and triethylamine (0.74 g) in methylene chloride (30 ml). The mixture isstirred at room temperature for 30 minutes, washed with water, driedover sodium sulfate and evaporated. The residue is crystallized fromethyl acetate to give the title compound, mp 225°-228° C.

In the same manner but replacing2-amino-5-[(2-carboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one with anequivalent amount of5-amino-2-[(2-carboxyphenyl)thio]-7-methyl-2,4,6-cycloheptatrien-1-oneor2-methylamino-6-[(2-carboxyphenyl)thio]-4-phenyl-2,4,6-cycloheptarien-1-one,[[5-oxo-4-[(2-carboxyphenyl)thio]-6-methyl-1,3,6-cycloheptatrien-1-yl]-amino]oxo-aceticacid ethyl ester and[N-[7-oxo-5-[(2-carboxyphenyl)thio]-3-phenyl-1,3,5-cycloheptatrien-1-yl]-N-methylamino]oxo-aceticacid ethyl are obtained, respectively.

EXAMPLE 9[[3-[N-[(4-Methylphenyl)sulfonyl]-N-methylamino]-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticAcid Ethyl Ester; I [R¹ = NH-CO-COOC₂ H₅ ; R², R³, R⁴ and R⁵ = H and R⁶= [N-(4-methylphenyl)sulfonyl]-N-methylamino]

a. A mixture of2-hydroxy-3-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-one(14.5 g), potassium carbonate (12.5 g), dimethyl sulfate (12.5 g) and2-butanone (145 ml) is heated at reflux for 1 hour. The mixture isfiltered and the precipitate is washed with water and suspended in ethylactate. Hydrochloric acid (10%) is added until the solution is acidic.The organic phase is collected and dried over sodium sulfate.Evaporation of the solvent and crystallization of the residue from ethylacetate-hexane gives2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one,mp 163°-164° C. The above filtrate is evaporated and the residue issubjected to chromatography on silica gel using ethyl acetate-hexane(3:1). Evaporation of the eluates are crystallization of the residuefrom ethyl acetate gives2-methoxy-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,mp 101°-102° C and2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,mp 94.5° C.

b. A solution at -25° C of2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6cycloheptatrien-1-one(described above, 4.0 g) in methanol (40 ml) is saturated with ammoniagas and heated in a pressure bottle at 80° C for 4 hours. The solutionis cooled to -70° C, the bottle is opened and the solvent is evaporatedto yield2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,mp 221°-222° C.

In the same manner but replacing2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-onewith an equivalent amount of2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-oneor2-methoxy-3-[N-[(4-methylphenyl)-sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,2-amino-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-oneand2-amino-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1oneare obtained respectively.

c. A solution of ethyl oxalyl chloride (0.475 g) in methylene chloride(10 ml) is added dropwise to a solution of2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatriene-1-one(described above, 0.87 g) and triethylamino (0.354 g) in methylenechloride (10 ml). The solution is stirred at room temperature for 2hours, washed with water, dried over sodium sulfate and evaporated. Theresidue is crystallized from ethyl acetate-hexane to give the titlecompound, mp 148.5°-150° C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

In the same manner but replacing2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-onewith an equivalent amount of2-amino-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-oneor2-amino-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,[[3-[N-[(4-methylphenyl)sulfonyl]amino]-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticacid ethyl ester and[[7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticacid ethyl ester are obtained respectively.

In the same manner but replacing dimethyl sulfate with an equivalentamount of diethyl sulfate, the title compound is obtained.

EXAMPLE 10[(3-Methylamino-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic AcidEthyl Ester; I (R¹ = NH-CO-COOC₂ H₅ ; R², R³, R⁴ and R⁵ = H and R⁶ =NHCH₃)

A solution of2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one[described in Example 9 (b), 2.53 g] in conc. sulfuric acid (25 ml) isheated at 75° C for 1 hour and added to ice. The ice-mixture isneutralized with sat. sodium carbonate solution and extracted withchloroform. The organic extract is dried over sodium sulfate andevaporated to give 2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one.

A solution of ethyl oxalyl chloride (2.46 g) in methylene chloride (10ml) is added dropwise to a solution of2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one (1.32 g) andtriethylamine (1.95 g) in methylene chloride (15 ml). The mixture isheated at reflux for 3 hours, washed with water, dried over sodiumsulfate and evaporated. The residue is subjected to chromatography onsilica gel using acetone-hexane (3:7) and the eluates are evaporated togive the title compound, mp 178°-181° C.

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl or propyl oxalyl chloride, the methyl andpropyl esters of the title compound are obtained.

In the same manner but replacing2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-onewith an equivalent amount of2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one[described in Example(9a)],[(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidethyl ester, mp 164°-167° C, is obtained.

By following a procedure selected from Examples 1 to 10 using theappropriate starting material of formula II and the appropriate compoundof formula III in which R¹⁰ is lower alkyl, other compounds of formula Iin which at least one of R¹ and R⁴ is NR⁹ COCOOR¹⁰ wherein R⁹ is asdefined herein and R¹⁰ is lower alkyl are obtained. Examples of thelatter compounds of formula I are listed as products in Table I togetherwith the appropriate starting material of formula II used for thepreparation of the compound of formula I.

                                      TABLE1                                      __________________________________________________________________________                                   Product:                                                                      [(prefix listed below)-cycloheptatrien-l-yl                                   )amino]-                                       Starting Material of Formula 11                                                                              oxo-acetic acid (suffix listed below)]         Ex.                                                                              R.sup.11                                                                           R.sup.12                                                                          R.sup.13                                                                          R.sup.14                                                                           R.sup.15                                                                           R.sup.16                                                                           Prefix/Suffix                                  __________________________________________________________________________    11 H    H   H   NH.sub.2                                                                           Br   CH.sub.3                                                                           [(2-bromo-3-methyl-4-oxo-2,5,7 / / ethyl                                      ester                                          12 NHCH.sub.3                                                                         H   CH.sub.3                                                                          H    C.sub.6 H.sub.5                                                                    H    [N-methyl-N-(6-methyl-2-oxo-4-phenyl-3,5,7                                    / / ethyl ester                                13 NH.sub.2                                                                           H   H   OC.sub.2 H.sub.5                                                                   H    I. [(5-ethoxy-3-iodo-2-oxo-3,5,7 / / methyl                                   ester                                               14 NH.sub.2                                                                           H   H   NHCH.sub.3                                                                         CH.sub.3                                                                           H    [[5-[N-(2-ethoxy-1,2-dioxoethyl)methylamino                                   ]-4-methyl-                                                                   2-oxo-3,5,7// ethyl ester                      15 H    C.sub.3 H.sub.7                                                                   H   NH.sub.2                                                                           H    CF.sub.3                                                                           [(2-oxo-7-propyl-3-trifluoromethyl-3,5,7                                      // methyl ester                                16 NH.sub.2                                                                           C.sub.5 H.sub.1                                                                   H   H    H    OC.sub.3 H.sub.7                                                                   [(2-oxo-7-pentyl-3-propoxy-3,5,7 // propyl                                    ester                                          17 NHC.sub.3 H.sub.9                                                                  H   OH  F    H    H    [N-butyl-N-(5-fluoro-6-hydroxy-2-oxo-3,5,7                                    // propyl ester                                18 NHC.sub.3 H.sub.7                                                                  H   H   NH.sub.2                                                                           H    OC.sub.6 H.sub.5                                                                   [[5-[N-(2-ethoxy-1,2-dioxoethyl)propylamino                                   ] -4-oxo-3-                                                                   phenoxy-1,5,7// ethyl ester                    19 OC.sub.2 H.sub.5                                                                   H   C.sub.4 H.sub.9                                                                   NHC.sub.2 H.sub.5                                                                  H    H    [N-ethyl-N-(7-butyl-5-ethoxy-4-xo-2,5,7 //                                    methyl ester                                   20 H    OCH.sub.3                                                                         H   NH.sub.2                                                                           H    OH   [(3-hydroxy-6-methoxy-4-oxo-2,5,7 // ethyl                                    ester                                          21 H    SH  H   NH.sub.2                                                                           C.sub.2 H.sub.5                                                                    H    [(2-ethyl-6-mercapto-4-oxo-2,5,7 // propyl                                    ester                                          22 NH.sub.2                                                                           H   Cl  H    OH   H    [(6-chloro-4-hydroxy-2-oxo-3,5,7 // ethyl                                     ester                                          23 NHC.sub.4 H.sub.9                                                                  H   OC.sub.6 H.sub.5                                                                  H    H    SH   [N-butyl-N-(3-mercapto-2-oxo-6-phenoxy-3,5,                                   7 //                                                                          methyl ester                                   24 CF.sub.3                                                                           Br  H   NH.sub.2                                                                           H    H    [(6-bromo-4-oxo-5-trifluoromethyl-2,5,7                                       //                                                                            ethyl ester                                    25 NH.sub.2                                                                           H   H   N(CH.sub.3).sub.2                                                                  Cl   H    [(4-chloro-5-dimethylamino-2-oxo-3,5,7 //                                     ethyl ester                                    26 NH.sub.2                                                                           H   OC.sub.2 H.sub.5                                                                  H    H    N(C.sub.3 H.sub.7).sub.2                                                           [(6-ethoxy-3-dipropylamino-2-oxo-3,5,7 //                                     methyl ester                                   27 N(C.sub.2 H.sub.5).sub.2                                                           CH.sub.3                                                                          OH  NH.sub.2                                                                           H    H    [(5-diethylamino-7-hydroxy-6-methyl-4-oxo-2                                   ,5,7 //                                                                       ethtyl ester                                   28 NH.sub. 2                                                                          SH  H   H    N(CH.sub.3)                                                                        H    [[4-(N-ethyl-N-methylamino)-7-mercapto-2-ox                                   o-3,5,7                                                             (C.sub.2 H.sub.5)                                                                       // propyl ester                                __________________________________________________________________________

EXAMPLE 29 [(5-Methoxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-aceticAcid Methyl Ester; I (R¹ = OCH₃ ; R², R³, R⁵ and R⁶ = H and R⁴ =NH-CO-COOCH₃)

[(5-Hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester (4.1 g, described in Example 4) is dissolved in boiling methanol(500 ml) and the mixture is cooled to room temperature and reacted witha solution of diazomethane in ether (ca. 351 ml). The reaction mixtureis stirred for one hour until all the solid is reacted withdiazomethane. The solvent is removed under reduced pressure and theresidue is crystallized from methanol to give the title compound, mp198°-200° C.

In the same manner but replacing[(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester with an equivalent amount of[(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester (described in Example 5),[(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidmethyl ester is obtained.

EXAMPLE 30 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid; I(R¹ = NH-CO-COOH and R², R³, R⁴, R⁵ and R⁶ = H)

A solution of potassium acetate (0.98 g) in water (5 ml) is added to asuspension of [(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidethyl ester (2.21 g, described in Example 1) in water (15 ml) and theresulting mixture is heated at 100° C for 5 hours. The mixture iscooled, diluted with water, charcoalized and filtered. The filtrate isacidified with 10% hydrochloric acid and the precipitate is collected togive the title compound, mp 193°-194° C.

In the same manner but replacing potassium acetate with an equivalentamount of sodium bicarbonate or potassium carbonate, the title compoundis obtained.

In the same manner but replacing the starting material[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl esterwith other esters of formula I, other acids of formula I are obtained.For example, replacing the starting material with the title compound ofExamples 2,3,5,6,7,8,14 and 23, the following acids of formula I areobtained respectively:[(3-bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid,[(3-phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid,[(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid,2,2'[(2-oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-aceticacid], [(6-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-aceticacid, [(3-methylamino-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-aceticacid,[[5-[N-(carboxycarbonyl)-N-methylamino]-4-methyl-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticacid and[N-(3-mercapto-2-oxo-6-phenoxy-3,5,7-cycloheptatrien-1-yl)-N-butylamino]oxo-aceticacid.

EXAMPLE 31 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic AcidPentyl Ester; I (R¹ = NH-CO-COOC₅ H₁₁ and R², R³, R⁴, R⁵ and R⁶ = H

A solution of [(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid(1.54 g, described in Example 30) and potassium carbonate (0.82 g) indimethylsulfoxide (8 ml) is stirred at room temperature for 15 minutes.A solution of 5 -bromopentane (1.52 ml) in dimethylsulfoxide (8 ml) isadded and the resulting mixture is stirred at 80° C for 40 minutes. Themixture is cooled to room temperature and poured over ice. The mixtureis stirred for ten minutes and the precipitate is collected byfiltration. The precipitate is dissolved in ether, treated with charcoaland crystallized by the addition of hexane to give the title compound,mp 87°-89° C.

In the same manner but replacing the alkyl halide, 5-bromopentane, withan equivalent amount of 2-bromopropane or 2-bromo-2-methylpropane,[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 1-methylethylester, mp 91°-93° C and[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid1,1-dimethylethyl ester, mp 76°-78° C, are obtained respectively.

In the same manner but replacing the starting material,[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, with otheracids of formula I and using an appropriate alkyl halide other esters offormula I are obtained. For example, replacing the starting materialwith an acid described in Example 30, the following esters of formula Iare obtained.[(3-bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid2-methylpropyl ester,[(3-phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid hexylester,2,2'-[(2-oxo,3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-aceticacid]dipropyl ester,[(6-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid1,1-dimethylethyl ester and [[5-[N-2-butoxy-1,2-dioxoethyl)methylamino]-4-methyl-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-acetic acidbutyl ester.

We claim:
 1. A compound of formula I ##STR4## in which R¹ and R⁴ are thesame or different selected from the group consisting of hydrogen, halo,trifluoromethyl, lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy,mercapto, (2-carboxyphenyl)thio, NR⁷ R⁸ wherein R⁷ and R⁸ each ishydrogen or lower alkyl or R⁷ is lower alkyl and R⁸ isp-toluenesulfonyl, and a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ andR¹⁰ each is hydrogen or lower alkyl; and R², R³, R⁵ and R⁶ are the sameor different selected from the group consisting of hydrogen, halo,trifluoromethyl, lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy,mercapto, (2-carboxyphenyl)thio and NR⁷ R⁸ wherein R⁷ and R⁸ each ishydrogen or lower alkyl or R⁷ is lower alkyl and R⁸ isp-toluenesulfonyl; with the proviso that at least one of R¹ and R⁴ mustbe a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ and R¹⁰ are as definedherein; or a therapeutically acceptable salt thereof.
 2. A compound offormula 1 ##STR5## in which a. R¹ is a radical of formula NR⁹ COCOOR¹⁰in which R⁹ and R¹⁰ each is hydrogen or lower alkyl, and R², R³, R⁴, R⁵and R⁶ are the same or different selected from the group consisting ofhydrogen, lower alkoxy and hydroxy;b. R⁴ is a radical of formula NR⁹COCOOR¹⁰ in which R⁹ and R¹⁰ each is hydrogen or lower alkyl, and R¹,R², R³, R⁵ and R⁶ are the same or different selected from the groupconsisting of hydrogen, lower alkoxy and hydroxy; or c. R¹ and R⁴ are aradical of formula NR⁹ COCOOR¹⁰ wherein R⁹ and R¹⁰ each is hydrogen orlower alkyl, and R², R³, R⁵ and R⁶ are the same or different selectedfrom the group consisting of hydrogen, lower alkoxy and hydroxy; or atherapeutically acceptable salt thereof.
 3. A compound of formula 1##STR6## in which a. R¹ is a radical of formula NR⁹ COCOOR¹⁰ in which R⁹and R¹⁰ each is hydrogen or lower alkyl, and R², R³, R⁴, R⁵ and R⁶ arethe same or different selected from the group consisting of hydrogen,lower alkoxy and hydroxy, with the proviso that at least three of R²,R³, R⁴, R⁵ and R⁶ are hydrogen;b. R⁴ is a radical of formula NR⁹COCOOR¹⁰ in which R⁹ and R¹⁰ each is hydrogen or lower alkyl, and R¹,R², R³, R⁵ and R⁶ are the same or different selected from the groupconsisting of hydrogen, lower alkoxy and hydroxy, with the proviso thatat least three of R¹, R², R³, R⁵ and R⁶ are hydrogen; or c. R¹ and R⁴are a radical of formula NR⁹ COCOOR¹⁰ wherein R⁹ and R¹⁰ each ishydrogen or lower alkyl, and R², R³, R⁵ and R⁶ are the same or differentselected from the group consisting of hydrogen, lower alkoxy andhydroxy, with the proviso that at least two of R², R³, R⁵ and R⁶ arehydrogen, or a therapeutically acceptable salt thereof.
 4. A compound offormula 1 ##STR7## in which a. R¹ is a radical of formula NR⁹ COCOOR¹⁰in which R⁹ and R¹⁰ each is hydrogen or lower alkyl, and R², R³, R⁴, R⁵and R⁶ are hydrogen; orb. R¹ and R⁴ are a radical of formula NR⁹COCOOR¹⁰ in which R⁹ and R¹⁰ each is hydrogen or lower alkyl, and R²,R³, R⁵ and R⁶ are hydrogen, or a therapeutically acceptable saltthereof.
 5. [(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidethyl ester, as claimed in claim
 1. 6.[(2-Oxo-3,5,7-cycloheptatrien-1-yl)-N-methylamino]oxo-acetic acid ethylester, as claimed in claim
 1. 7.[(3-Bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 8.[(5-Chloro-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 9.[(3-Phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 10.[(7-Phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 11.[(5-Hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 12.[(3-Hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 13.2,2'[(2-Oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-aceticacid] diethyl ester, as claimed in claim
 1. 14.[(5-Methoxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidMethyl Ester, as claimed in claim
 1. 15.[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid pentyl ester,as claimed in claim
 1. 16.[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 1-methylethylester, as claimed in claim
 1. 17.[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid,1,1-dimethylethyl ester, as claimed in claim
 1. 18.[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, as claimed inclaim
 1. 19.[[3-[N-[(4-Methylphenyl)sulfonyl]-N-methylamino]-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticacid ethyl ester, as claimed in claim
 1. 20.[(3-Methylamino-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acidethyl ester, as claimed in claim
 1. 21.[(3-Methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 22.[(6-Methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 23.[(4-Methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethylester, as claimed in claim
 1. 24.[[7-oxo-4-[(2-carboxyphenyl)thio]-1,3,5-cycloheptatrien-1-yl)amino]oxo-aceticacid ethyl ester, as claimed in claim
 1. 25. A method for suppressingallergic manifestations of anaphylactic reactions and atopichypersensitivity in a mammal which comprises administering to saidmammal an effective amount of a compound of claim 1, or atherapeutically acceptable salt thereof.
 26. A pharmaceuticalcomposition useful in suppressing allergic manifestations ofanaphylactic reactions and atopic hypersensitivity comprising a compoundof claim 1, or a therapeutically acceptable salt thereof, and apharmaceutically acceptable carrier.